The following documents are all incorporated herein by reference in their entireties, although none is admitted to be prior or relevant art. Collectively they reflect that there is a current and long-felt need for, and past failure of success as relates to, adequate microcassette fabrication and microfluidics, not only from a cost and ease of fabrication and reproducibility standpoint, but also from the standpoint that such systems are typically restricted to laminar flow and feature inefficient mixing compounded by gaseous bubble formation that obstructs or restricts flow and diffusion. The present invention, depending on aspect and embodiment, provides useful solutions to one or more of these historic deficiencies.
Woolley et al. (1996) report functional integration of PCR amplification and capillary electrophoresis in a microfabricated DNA analysis device. Anal. Chem., 68:40814086. The chips are generated by photolithography and etching of silicone wafers. The prospects for electrophoretic valving and active microfabricated valves made from polymer diaphragms are also discussed.
Martynova et al. (1997) report fabrication of plastic (poly(methylmethacrylate) (PMMA)) microfluid channels by imprinting methods for use in electrophoretic and chromatographic applications. Anal. Chem., 69:4783-4789. Mechanical pumping is referenced, as are the fabrication techniques of casting, molding, laser ablating and machining plastic. Bubble entrapment is noted as a problem that can be solved by heating.
Roberts et al. (1997) report micro channel construction using UV laser machined polymer substrates (e.g., polystyrene, polycarbonate, cellulose acetate, and poly(ethylene terephthalate) (PET) for the development of microdiagnostic systems. Anal. Chem., 69:2035-2042. The article also discusses laminate sealing. Pump and valving are not addressed.
Burns et al. (1998) report an integrated nanoliter DNA analysis device made of a glass and silicone substrate and containing microfabricated channels, heaters, temperature sensors, and fluorescence detectors. Science, vol. 282, pp. 484-487. The device is made using photolithography and is reportedly capable of measuring, mixing, amplifying and digesting DNA.
Kopp et al. (1998) report continuous-flow PCR on a glass microchip. Science, vol. 280, pp. 1046-1048.
Waters et al. (1998) report a microchip device for cell lysis, multiplex PCR amplification, and electrophoretic sizing and fluorescence-based detection. Anal. Chem., 70:158-162. Microchannels are polymer-etched and 50 um wide by 10.4 um deep. Valving, pumps, and the identity of the polymer substrate are not addressed.
Duffy et al. (1999) report microfabricated centrifugal microfluidic systems having microscopic channels formed in a plastic disk by casting molded PDMS or machining pmethylmethylacrylate. Anal. Chem. 71:4669-4678. The channels are reported to have diameters of 5 um-0.5 mm and depths of 16 um-3 mm.
Anderson, J. et al. (2000) report fabrication of three-dimensional microfluidic systems in PDMS using “membrane sandwiches”, in which thin membranes having channel structures molded on each face are fixed under pressure between two thicker, flat slabs. Anal. Chem. 72, pp 3158-3164.
Anderson, R. et al. (2000) report a miniaturized integrated polycarbonate device (“disposable cartridge”) the size of a credit card for automated multistep genetic assays. Nucl. Acid. Res., Vol. 28, No. 12, pp. i-vi. The device employs laminate valves made out of a 0.01 mm thick mylar held in place by ultrasonic welding or adhesives. Fluids are moved therethrough using a pneumatic diaphragm valve and vacuum. Porous hydrophobic membranes are reported that allow the passage of gas but not liquids.
Barker et al. (2000) report polystyrene, PDMS, polycarbonate and polyethylene terephthalate glycol (PETG) plastic microfluidic devices having surfaces modified with polyelectrolyte multilayers (PEMs). Anal. Chem. 72: 4899-4903.
Beebe et al. (2000) report a PDMS microfluidics platform that combines liquid-phase photopolymerization cartridges using lithography, channels, pH-actuated hydrogel valving, and sensors. PNAS, vol. 95, no. 25, pp. 13488-13493.
Liu et al. (2000) report chaotic advection passive mixing in a three-dimensional serpentine microchannel having a C-shaped repeating unit. J. Micro-electromech. Sys., Vol. 9 No. 2, pp. 190-197. The device is fabricated in a silicon wafer using a double-sided KOH we-etching. Discussed are active mixing techniques versus passive techniques, the relative sophistication and difficulties presented by the former, and the need for at least one such mechanism when small dimension (tens of micrometers) channels are employed. Also discussed is the fluid dynamics principle of Reynolds numbers, Re, =Q/A (flow rate over cross-sectional area)×Dh/ν (hydraulic diameter of channel over kinetic viscosity of fluid. The repeating C— units emanate away from the inlet and toward a distinct outlet.
Oleschuck et al. (2000) report trapping of bead-based reagents within microfluidic systems and on-chip solid-phase extraction and electrochromatography, coupled with electrofluorescence detection. Anal. Chem., 72:585-590. The system is made of etched glass and features continuous, valveless flow.
Unger et al. (2000) report on monolithic microfabricated valves and pumps for multilayer soft lithography. Science 288; 113-116. Soft lithography is described as an alternative to silicon-based micromachining and uses replica molding of nontraditional elastomeric materials to fabricate stamps and microfluidic channels, with advantages afforded in terms of rapid prototyping, ease of fabrication and biocompatibility. Systems containing on-off valves, switching valves, and pumps made entirely out of elastomer are described. Those systems include microlectromechanical structures (“MEMS”) that are either bulk or surface micromachined from silica or other semiconductor-type materials (e.g., polysilicon, metals, silicon nitride, silicon dioxide, etc.), with the latter sequentially applied and patterned in 3D structures, or else replication molding-based by patterned curing of elastomeric material (“soft lithography”). The elastomer used is a two-component addition-cured silicon rubber fused by hermetic sealing and irreversible bonding. Up to seven (7) independent layers are combined into one using this technique. Each of the layers and resulting device is monolithic (i.e., all made from the same material). The valves described are crossed-channel in architecture, 100 um wide by 10 um high, mediated by polymer membrane typically 30 um in thickness, and sealed with a glass bottom layer. The flexibility and durability of the layers permits the repeated opening and closing of valves upon pneumatic actuation without appreciable fatigue. Tubular flow channels are urged as opposed to rectangular or other shapes, and there is also discussion of the problem of electrolytic bubble formation and avoidance thereof. A peristaltic pump consisting of three valves arranged in a single channel is also reported. The figures also show unidirectional flow in which the inlets are remote from the “waste” outlet points.
Xu et al. (2000) report a room-temperature imprinting method for microchannel fabrication in PMMA. Anal. Chem., 72:1930-1933. PDMS film is used to seal the channels, which are imprinted from a micromachined silicone template. Pumping and valving are not per se addressed.
Chabinyc et al. (2001) report an integrated fluorescence detection system in combination with disposable PDMS microfluidic implements. Anal. Chem., 73:44914498.
Gioradano et al. (2001) report use of the polymerase chain reaction (PCR) in polyimide microchips using 1.7 ul volumes and IR-mediated thermocycling. Anal. Biochem., 291:124-132.
Ismagilov et al. (2001) report multi-phase laminar fluid flow and “switching” through a three-dimensional elastomeric microstructure formed by two microfluidic channels, fabricated in layers that contact one another face-to-face (typically at a 90 angle), with the fluid flows in tangential contact. Anal. Chem. 73:4682-4687. There is no discussion of valves or valving per se, pressure is administered by syringe, polydimethylsiloxane (PDMS) membranes of 4-5 mm in dimension are used in construction, and channels of ˜25-200 μm operative height, 100-400 μm operative width, and 2-4 cm operative length are used. Further, the inlet and outlet ports are remote to another, the adhesion of the individual layers is accomplished by oxidizing the mating surfaces in an air plasma system for approximately 1 minute, and a glass cover slip is also used.
Kamholz and Yager (2001) theoretically analyze molecular diffusion in pressure-driven laminar flow in microfluidic channels. Biophys. J., 80:155-160. The authors conclude there is reduced diffusivity in microfluidic systems, including, e.g., systems employing self-assembling monolayers (SAMS).
Lachner et al. (2001) report the advantages of planar microchip capillary electrophoresis in conjunction with electrochemistry, including miniaturization potential while preserving sensitivity. Electrophoresis 22:2526-2536. Emphasis is on the selective grounding of a detection reservoir relative to a “separation channel” into which sample is first introduced. The system also features sample waste and buffer reservoirs, as well as a high-voltage source to effect separation. By definition, the system depends on electric field establishment for sample migration and there is no circulation or recirculation of liquid sample. These systems feature glass or plastic chips, with the latter fashioned from laser ablation or injection molding techniques, and a variety of electrode surfaces, including carbon, platinum, palladium, copper and gold. Applications discussed include those for separation and detection of catecholes, amino acids, peptides, carbohydrates, nitroaromatics, PCR products, organophosphates and hydrazines. As expected for electrophoretic applications, separation of PCR products is coordinated with restriction enzyme digestion.
Whitesides et al. (2001) review soft lithograpy techniques and the implications for microfabrication and biochip patterning and configuration. Annu. Rev. Biomed., 3:335-73. Soft lithography, as opposed to photolithography, is based on printing and molding using elastomeric stamps with patterns of interest in bas-relief. PDMS is a substrate of choice that is patterned with self-assembling monolayers (SAMs) and microcontact printing (uCP). Membrane-stacking is noted as a method of synthesizing and configuring 3-dimensional microfluidic structures. Pumps (including pneumatic) and soft PDMS membrane flap valving is also briefly noted.
Yuen et al. (2001) report a microchip module of blood sample preparation and nucleic acid amplification reactions. Genome Res., 11:405-412. The module is a computer numerical control-machined Plexiglas microchip. A syringe pump is used in tandem with valving.
Auroux et al. (2002) review micro analysis systems for the period 1997 to 2002. Anal. Chem. 74: 2637-2652.
Beebe et al. (2002) review microfluidics in general and the fabrication of valves, mixers and pumps for the same as of 2002. Annu. Rev. Biomed. Eng. 4:261-86. Micromatching, soft lithography, embossing, in situ construction, injection molding and laser ablation are discussed, as well as the advantages and disadvantages attendant thereto.
Jeon et al. (2002). Report design and fabrication of integrated passive valves and pumps for flexible polymer 3-dimensional microfluidic systems. Biomed Microdevices 4:117-121.
Johnson et al. (2002) report rapid microfluidic mixing in preformed T-microchannel imprinted in a hot-imprinted polycarbonate silicon stamped substrate and modified with a pulsed UV excimer laser to create slanted wells at the junction. Anal. Chem. 74:45-51. PETG “lids” were sealed to the PC by heat-bonding.
Stroock et al. (2002) report chaotic mixers for microchannels. Science 295: 647-651. The difference between laminar and turbulent flow is discussed in terms of efficient mixing, with the former (characteristic of systems having channels of dimension ˜100 μm or less) described as less efficient and characteristic of microfluidic systems in general. Stroock et al.'s solution is to employ textured relief structures deposited by planar lithographic techniques inside PDMS microfluidic channels in order to impart differential resistance across varied topographic surfaces, thereby improving passive mixing in the process.
Klank et al. (2002) report CO2 laser micromachining and back-end processing for rapid production of PMMA-based microfluidic systems. Lab Chip, 2:242-246.
McDonald and Whitesides (2002) report poly(dimethylsiloxane) (PDMS) as a useful material for fabricating microfluidic devices. Accounts of Chemical Res., vol. 35, no. 7, pp. 491499. Silicone adhesive tapes are noted for their ability to reversibly effect water-tight binding between different PDMS components. 3-D “membrane sandwich” fabrication by stacking multiple layers is also discussed, as is the ability to configure the devices with chambers that fit pipette tips.
Pugmire et al. (2002) report surface characterization of laser-ablated polymers used for microfluidics. Anal. Chem., 74:871-878. Electroosmotic flow comparisons are made between PMMA, PETG, PVC and PC after ablation under different gaseous conditions. Pumping and valving are not addressed.
Qi et al. (2002) report high-aspect-ration microstructures (HARMS) in microfluidic devices fabricated from PMMA using hot-embossing with integrated sampling capillary and fiber optics for fluorescence detection. Lab Chip, 2:88-95. Aspect ratio is described as the ratio of feature height to lateral dimension. Pumping and valving are not addressed.
Reyes et al. (2002) briefly review the historical evolution of micro total analysis systems (“uTAS”; synonymous with “lab on a chip”) theory and technology, including microfabrication, bonding, surface modification, design, interfaces and connections, microvalves and flow control, and micropumps. Anal. Chem. 74:2623-2636. Construction materials noted include, e.g., PDMS, PMMA, PC, poly(ethyleneterephthalate) (PET), and poly(tetrafluoroethylene) (Teflon®). Valving and pumping are generally discussed on page 2631 et seq. Passive membraneous check valves are noted, as well as flap, lever and duckbill varieties.
Wang, J. (2002) reports on electrochemical detection in microscale analytical systems and how such systems offer possible advantages by way of miniaturization, portability and, more tenuously, disposability. Talanta 56:223-231. Emphasis is again on electrophoretic separations and sample reservoir to waste reservoir directionality and flow, with the reservoirs made of PDMS/glass. Included is discussion of capillary electrophoretic (CE) systems, micromachining and ablation techniques, as well as discussion of different electrode types/compositions and forms of electronic detection, e.g., fixed-potential/current monitoring (amperometric) and voltammetry. Detection of nucleic acids is discussed using intercalating iron-phenanthroline redox markers.
Breadmore et al. (2003) report microchip-based purification of DNA from biological samples. Anal. Chem. 75:1880-1886.
Fiorini et al. (2003) report fabrication of thermoset polyester microfluidic devices and embossing masters using rapid prototyped polydimethylsiloxane (PDMS) molds. Lab Chip, 3:158-163.
Glasgow and Aubry (2003) report enhanced microfluidic mixing using time pulsing. Lab Chip, 3:114-120. Mixing is accomplished by time varying and pulsing fluid flow using, e.g., variable channel dimensions. Bubble entrapment is stated as a problem to be avoided. The substrate used is not identified and there is no discussion of venting or valving.
Jensen et al. (2003) report microstructure fabrication in poly(methyl methylacrylate) (PMMA) with a CO2 laser system, including raster scanning to produce cavities 50 um wide and 200 um deep. Lab Chip, 3:302-307.
Koh et al. (2003) report integrated PCR, valving and electrophoresis in a plastic device for bacterial detection. Anal. Chem. 75:45914598. The device is made from cyclic polyolefin having graphite ink electrodes and photopatterned gel domains that function as passive valves. Detection is optical and accomplished using laser-induced fluorescence of an interchalating dye. Volumes used were 29-84 nL.
Kricka and Wilding (2003) review microchip PCR systems bearing serpentine channels and fabricated from molded PDMS, micromachined polycarbonate or assembled layers of ceramic tape, held together, e.g., by use of adhesives. Anal. Bioanal. Chem. 377:820-825. A host of passivation agents are also discussed that avoid adverse surface interactions, including, e.g., silicon oxide, PDMS, polypropylene, BSA, and polyvinylpyrrolidone.
Landers (2003) reports inter alia on the potential for performing single nucleotide polymorphism (SNP) diagnostics on electrophoretic microchips, preferably using optical detection on capillary based systems. Anal. Chem., 75:2919-2927. See, e.g., pp. 2922.
Liu et al. (2003) report sophisticated microfluidic PCR systems devised of multilayer elastomeric PDMS formed using photolithography and active pumping and valving schemes. Anal. Chem. 75:4718-4723.
Wang et al. (2003) report low-density microarrays assembled in microfluidic chips fabricated from hot-embossed PMMA for the detection of low-abundant DNA mutations. Anal. Chem., 75:1130-1140. Appropriate ligand linking chemistry is also addressed.
Buch et al. (2004) report DNA mutation detection in a modular polycarbonate microfluidic network using temperature gradient gel electrophoresis. Anal. Chem. 76:874-881. One module is embossed with microchannels and the other contains a tapered microheater lithographically patterned along with an array of temperature sensors.
Gustafsson et al. (2004) report integrated peptide sample preparation and MALDI Mass Spectometry on a Microfluidic Compact Disk, in which sample fluid is pushed using centripetal force. Anal. Chem. 76:345-350.
Hashimoto et al. (2004) report rapid PCR in a continuous flow embossed polycarbonate device. Lab Chip, 4:638-645. Microchannel dimensions used were 6 cm (L)×50 um (W)×150 um (H).
Howell et al. (2004) report on fluid dynamics principles and the design and evaluation of a Dean vortex-based micromixer on a machined PMMA chip. Lab chip, 4:663-669. A double-sided adhesive tape is used to fix the machined chip to a glass slide and bubble avoidance is urged.
Lagally et al. (2004) report an integrated portable genetic analysis microsystem for pathogen/infectious disease detection using PCR, electrophoresis and laser-excited fluorescence detection. Anal. Chem., 76:3162-3170. The system is said to be of etched glass wafer design and contain active solenoid PDMS “membrane valves”, with one particular configuration possessing three such valves in series to collectively form a “diaphragm” pump. Sample volumes are 200 nL.
Lai et al. (2004) report a resin-gas injection packaging technique for bonding and surface modification of polymer-based microfluidic platforms such as glass, silicon, polyethylene, polystyrene poly(methyl methacrylate) (PMMA), polyamide, and polycarbonate. Anal. Chem., 76:1175-1183. Also noted are adhesive layer techniques and the problem of bubble accumulation/obstruction and the suggestion to use a vacuum to minimize such.
Laser and Santiago (2004) review micropump structures in J. Micromech. Microeng., 14:R35-R64. The detrimental problem of bubbles in microfluidic systems is noted repeatedly throughout, as is the general dearth of effective pumping systems in microfluidics systems. Despite this, reciprocating pneumatically-driven diaphragm pumps flanked by passive check valves are discussed in the context of multilayer constructions, see, e.g., FIG. 1. and §2.1, although diaphragms made out of soft polymer membranes are said to be a “concern” because of stability. Etching, micromachining and photolithography are also discussed as means of creating device channels and chambers.
Noerholm et al. (2004) report a disposable polycarbonate microfluid chip for online monitoring of microarray hybrizations. Lab Chip, 4:28-37. The chip is 25×76×1.1 mm in dimension and manufactured by micro injection molding. The chip is said to contain an inlet, a 10 ul hybridization chamber, a waster chamber and a vent to allow air to escape when sample is injected. Its utility is demonstrated using hybridization buffer, wash buffers, fluorescence-based detection and a computer controlled syringe pump. The system would appear to be capillary-action mediated, continued flow, non-recirculating and valveless. Use of plastic polymers is said to endow advantages by way of milling, laser ablation, hot embossing and injection molding. The use of adhesive tape in fashioning microstructures is also noted. The problem of bubble development is also noted but the vent used is located remote to the inlet and proximal to a waste chamber.
Schonfeld et al. (2004) report an optimized split-and-recombine (SAR) micro-mixer formed from milled PMMA and featuring active, uniform “chaotic” mixing. Lab Chip, 4:65-69.
Vilkner et al. (2004) review various micro total analysis systems (uTAS), including microfabrication, bonding techniques, microvalves and flow control, and micropumps. Anal. Chem., 76:3373-3386. Their review builds on that of Reyes (2002) and, in addition to discussing PDMS, PMMA, PC, poly(ethyleneterephthalate) (PET), and poly(tetrafluoroethylene) (Teflon®) as construction materials, and general valving, further includes discussion, e.g., of thermoresponsive hydrogel plugs and valving.
Yaralioglu et al. (2004) report ultrasonic mixing in PDMS microfluidic channels using integrated piezoelectric transducers. Anal. Chem., 76:3694-3698.
Fiorini and Chiu (2005) review disposable microfluidic device fabrication, function and application. BioTechniques vol. 38, no. 3, pp. 429-446. Methods of fabrication include replica and injection molding, embossing, and laser ablation. Fluid pumping and valving is also described, as is mixing and analyte separation and detection. Deformable membrane pressure pumps and valves are particularly discussed at pp. 434-5, as is the concept of pulsatile flow. Strategies for mixing include use of 3-dimensional serpentine channels. P. 435. Multilayer fabrication with plastics is also mentioned, as are electrochemical detection schemes and advantages attendant thereto, and nucleic acids as detectable analyte. pp. 438-9.
Howell et al. (2005) report a microfluidic mixer with grooves placed on the top and bottom of milled PMDA channels. Lab Chip, 5:524-530.
Klapperich et al. (2005) report hot-embossed fabrication of a cyclic polyolefin microfluidic device for on-chip isolation of nucleic acids onto silicon particles embedded in the device, followed by elution. Proc. ICMM2005, 3rd Int. Conf. on Microchannels and Minichannels. Toronto, CANADA.
Lee et al. (2005) report development of a passive 3-dimensional PDMS micromixer based on repeated fluid twisting and flattening of the channels, and its application to DNA purification. Anal. Bioanal. Chem., 383:776-782. Multi-layer stacking and multi-step photolithography are noted as device fabrication techniques. The system has discreet inlets and outlets that are remote relative to one another.
Roper et al. (2005) report advances in polymerase chain reaction (PCR) methodology on polycyclic olefin microfluidic chips using hydraulic valves and pneumatic pumps. Anal. Chem., 77:3887-3894. Reported reaction volumes are approximately 30 nl.
Skelley et al. (2005) report development and evaluation of a sophisticated capillary electrophoresis microdevice made of glass wafers and PDMS membranes for amino acid biomarker detection and analysis use on Mars. PNAS, vol. 102, no. 4, pp. 1041-1046. The device is vacuum driven and said to possess 34 individual membrane valves and 8 pumps. The wafers are 10 cm in diameter with 20 um deep×70 um wide×21.4 cm long channels.
Wang et al. (2005) report label-free detection of small-molecule-protein interactions using nanowire nanosensors (silicone; SiNW) and field effect transistors (FETs) on a surface plasma resonance (SPR)-like chip. PNAS, vol. 102, no. 9, pp. 3208-3212.
Whitesides et al. (2005) report a technique for storing and delivering a sequence of reagents to a microfluidic device. Abstract, Anal. Chem., 77(1):64-71. The technique makes use of cartridges of tubing filled by sequentially injecting plugs of reagents separated by air spacers.
Liu et al. (2006) report integrated microfluidic biochips for DNA microarray analysis by fluorescence imaging that contain electromechanical pumps, low-cost check valves, fluid channels and reagent storage containers. Expert Rev. Mol. Diagn., 6(2):253-261 (Abstract).
Soper et al. (2006) forecast point-of-care (POC) biosensor systems for cancer diagnostics/prognostics. Biosensors and Bioelectronics, 21:1932-1942. The article only generally speaks to the future of the field and the need for mass-production, low cost fabrication and specialized valving and pumping systems. Techniques contemplated for construction of such devices include injection molding, nanoprint lithography and hot-embossing.
U.S. Pat. Nos. 7,101,509 and 6,368,871 assigned to Cepheid share a common specification and collectively report and claim temperature controlled devices and methods for the manipulation of materials in a fluid sample using a plurality of microstructures bearing insulator films (selected from silicon dioxide, silicon carbide, silicon nitride, and electrically insulating polymers). The devices employ integrated loading chambers, reaction vessels, and aspirators in connection with the insulator-film bearing structures. Application of a voltage to the structures induces the desired electrophoretic separation and attraction, followed by washing and elution steps. U.S. Pat. Nos. 6,893,879, 6,664,104 and 6,403,037 assigned to Cepheid report and claim similar analyte flow, capture and elution techniques and devices.
U.S. Pat. No. 6,818,185 reports and claims a cartridge for conducting a chemical reaction that consists of a body having at least first and second channels formed therein, a reaction vessel extending from the body, a reaction chamber, an inlet port connected to the reaction chamber via an inlet channel, and an outlet port connected to the reaction chamber via an outlet channel. The inlet port of the vessel is connected to the first channel in the body, and the outlet port of the vessel is connected to the second channel in the body. The walls of the reaction chamber contain polymeric films, and vents for exhausting gas from the second channel are also described. The system also employs differential pressure sources for forcing sample through the system, which can further include thermal surfaces, heating elements, mixing and lysing chambers, and optically transmissive walls.
U.S. Pat. No. 6,374,684 reports a fluid control and processing system having a plurality of chambers and a valve body that includes a fluid sample processing region coupled with a fluid displacement region, the fluid displacement region depressurizable to draw fluid into the fluid displacement region and pressurizable to expel fluid from the fluid displacement region.
U.S. Pat. Nos. 6,830,936, 6,197,595, 6,043,080, 5,922,591, and 5,856,174, each entitled “Integrated nucleic acid diagnostic device” and assigned to Affymetrix, describe and/or claim diaphragm or controllable valve actuated miniature fluid flow systems for measuring and processing fluid samples. The systems described make use of a plurality of different chambers and channels, as well as inlet and vent ports. U.S. Pat. Nos. 6,733,977 and 6,168,948 are similar to these in content.
U.S. Pat. No. 7,223,363 (entitled “Method and System for Microfluidic Interfacing to Arrays”) and U.S. Pat. No. 7,235,400 (entitled “Laminated Microarray Interface Device”), each assigned to BioMicro Systems Inc., report pump-driven multi-laminate microfluidics systems having a gasket that defines the walls of a reaction chamber (e.g., serpentine), integrated passive valving, diaphragm and multiple bladder use to promote mixing, the possibility for sample (re)circulation and bubble elimination using an external pumping scheme, the relative positioning of multiple such devices such that there is a pitch of 9 mm between devices for ease of loading by a multipipetteman, and the merit of using construction materials that permit visualization/optical assessment of the system.
U.S. Pat. No. 5,063,081 (“Method of manufacturing a plurality of uniform microfabricated sensing devices having an immobilized ligand receptor”), U.S. Pat. No. 5,096,669 (“Disposable sensing device for real time fluid analysis”) and U.S. Pat. No. 5,124,661 (“Reusable test unit for simulating electrochemical sensor signals for quality assurance of portable blood analyzer instruments”) to I-STAT Corporation discuss inter alia use of a disposable cartridge system that makes use of an internal bladder to manipulate liquid sample.
Micronics, Inc. also holds numerous patents in the field of microfluidics including, e.g., U.S. Pat. No. 7,223,371 (“Microfluidic channel network device”), 6,743,399 (“Pumpless microfluidics”), 6,742,661 (“Well-plate microfluidics”), 6,581,899 (“Valve for use in microfluidic structures”), 6,557,427 (“Capillaries for fluid movement within microfluidic channels”) and 6,488,896 (“Microfluidic analysis cartridge”).
Numerous patents and papers published by Paul Yager are also germane to the topic of microfluidics and include, e.g., U.S. Pat. Nos. 5,716,852 and 5,972,710 (“Microfabricated diffusion-based chemical sensor”), 6,007,775 (“Multiple analyte diffusion-based chemical sensor”), 6,039,897 (“Multiple patterned structures on a single substrate fabricated by elastomeric micro-molding techniques”), 6,110,354 and 6,790,341 (“Microband electrode arrays”), 6,159,739 (“Device and method for 3-dimensional alignment of particles in microfabricated flow channels”), 6,454,945 (“Microfabricated devices and methods”), Sensors in Biomaterials Science: An Introductory Text, Ratner, B. D. and Hoffman, A. S., Eds. Academic Press, Inc., Orlando, (1996), Low Reynolds number micro-fluidic devices, Proceedings Hilton Head MEMS conference, Solid-State Sensor and Actuator Workshop, 105-108, (1996), Biotechnology at low Reynolds numbers, Biophysical Journal. 71 (6), 3430-3441, (1996), Integration of microelectrodes with etched microchannels for in-stream electrochemical analysis, Micro Total Analysis Systems, 105-108 (1998), Design of microfluidic sample preconditioning systems for detection of biological agents in environmental samples, SPIE Proceedings, 3515, 252-259 (1998), Whole blood diagnostics in standard gravity and microgravity by use of microfluidic structures (T-sensors), Mikrochimica Acta, 131, 75-83 (1999), A novel microfluidic mixer based on successive lamination, Micro Total Analysis Systems, Mesa Monographs, 495-498 (2003), On the importance of quality control in microfluidic device manufacturing, Micro Total Analysis Systems, Mesa Monographs, 1069-1072 (2003), Lab-on-a-chip and fluorescence sensing on the microscale, Fluorescence Sensors and Biosensors, R. B. Thompson, ed., ISBN 0-8247-2737-1, CRC Press, Boca Raton, Fla., c.400 pp (2005), Rapid, parallel-throughput, multiple analyte immunoassays with on-board controls on an inexpensive, disposable microfluidic device, Micro Total Analysis Systems, Vol. 2, Transducer Research Foundation, Pubs., 1000-1002 (2005), Recirculating flow accelerates DNA microarray hybridization in a microfluidic device, Lab on a Chip, in press.
Microfluidic systems and function is also addressed in patents and publications by Stanford's Stephen Quake, including U.S. Pat. No. 7,232,109 (“Electrostatic valves for microfluidic devices”), 7,216,671, 7,169,314, 7,144,616, 7,040,338, 6,929,030, 6,899,137, and 6,408,878 (“Microfabricated elastomeric valve and pump systems”), 7,143,785 (“Microfluidic large scale integration”), 6,960,437 (“Nucleic acid Microfabricated elastomeric valve and pump systems, 6,793,753 (“Method of making a microfabricated elastomeric valve”), 6,767,706 (“Integrated active flux microfluidic devices and methods”), and “A nanoliter-scale nucleic acid processor with parallel architecture,” Nat. Biotechnol, 22:4:435-9 (2004), “Solving the “world-to-chip” interface problem with a microfluidic matrix.” Anal. Chem., 75:18:4718-23 (2003), “Microfluidics in structural biology: smaller, faster em leader better.” Curr. Opin. Struct. Biol. 13:5:538-44 (2003), “Integrated nanoliter systems,” Nat. Biotechnol., 21:10:1179-83 (2003), “Microfabricated fountain pens for high-density DNA arrays,” Genome Res., 13:10:2348-52 (2003), “Microfluidic memory and control devices,” Science, 300:5621:955-8 (2003), “Microfluidic large-scale integration,” Science, 298:5593:580-4 (2002), “A nanoliter rotary device for polymerase chain reaction,” Electrophoresis, 23:10:1531-6 (2002), “Dynamic pattern formation in a vesicle-generating microfluidic device.” Phys. Rev. Lett. 86:18:4163-6 (2001), “Monolithic microfabricated valves and pumps by multilayer soft lithography.” Science, 288:5463:113-6 (2000); “From micro- to nanofabrication with soft materials,” Science, 290:5496:1536-40 (2000), and “A microfabricated device for sizing and sorting DNA molecules.” Proc. Natl. Acad. Sci. USA 96:1:11-3 (1999).
In addition to the foregoing work of others, commonly-owned U.S. Pat. Nos. 7,172,897, 6,960,467, 6,875,619, 6,833,267, 6,761,816, 6,642,046, 6,592,696, 6,572,830, 6,544,734, 6,432,723, and 6,361,958 also speak to microfluidics and microfluidics operations, including integration of individual electronic components and positionment into detection devices, including electrochemical detection devices.
As will be become apparent, the configuration and function of the above third party devices is different from aspects and embodiments of the inventions described herein in one or more of construction, valving, mixing, diaphragm positionment and function, bubble elimination, pump interfacing and recirculation design. These differences give rise to real advantages and prospects for the inventions described herein.